Abstract:
Intraventricular hemorrhage (IVH) has a very poor prognosis with mortality
rates between 80 and 100%, especially when all four ventricles are involved.
Neither surgical treatment (including radical removal of hematoma and simple
ventricular drainage) nor conservative therapy have proven to be effective
in changing this dismal picture. Fibrinolytic therapy has been reported
to improve overall outcome in several series. Both recombinant tissue plasminogen
activator (rt-PA) and urokinase (UK) have been used for this therapy. We
report the LSU experience with intrathecal UK over the past two years. (NerveCenter
4(2):2, 1999)
[Introduction | Case Material | Results | Discussion | References]
Introduction:
Spontaneous (nontraumatic) intraventricular hemorrhage (IVH), with or without
other hemorrhagic lesions (e.g. intraparenchymal or aneurysmal subarachnoid
hemorrhage) carries a grave prognosis with mortality rates between 80-100%
when all four ventricles are involved.(5,6,7,12) Neither surgical treatment
(including radical remoal of hematoma and simple ventricular drainage) nor
conservative therapy has proved to be effective in changing this dismal
picture.(15) It has been suggested that treatment with intraventricular
injection of fibrinolytic agents such as urokinase (UK) and recombinant
tissue plasminogen activator (rt-PA) may improve outcome and reduce the
need for shunting.(1,3,4,9,10,11) In the past two years, we have treated
four patients with intrathecal urokinase (IT UK) for IVH at LSUMC.
Case Material:
Four patients (mean age:45.2 years; range 25-65; 3 females and 1 male)
with IVH were treated with IT UK in the course of the past 2 years at LSUC.
Three of the 4 patients had a spontaneous IVH; one patient had a postoperative
IVH. All four patients were in a poor neurological condition at the time
of presentation: ranging from lethargic (2) to obtunded (2). All of them
had a hemorrhage involving all four ventricles with some degree of ventricular
dilatation. Three of 4 patients had a four vessel cerebral angiogram (showing
no vascular anomaly) prior to infusion of the IT UK. The patient with the
postoperative IVH did not have an angiogram. Two of the four patients had
a prior history of hypertension. The dose of IT UK infusion was similar
in all cases: 5000 units every 8 hours. UK was infused through a previously
placed ventriculostomy in the frontal horn of the lateral ventricle. After
infusion of the UK, the continuous drainage of CSF was stopped for 10-15
minutes. The ventriculostomy was left in place for an average of 5.5 days
(range:3-8 days). The UK was infused (every 8 hours) for an average of 4.7
days (range: 2-7 days).
Representative Case:
This 23 year old Vietnamese woman presented to the emergency room with
an acute onset of severe frontal headache and nausea/` vomiting. Initially
the patient was lethargic, but she rapidly became unresponsive. A cranial
CT scan showed an intraventricular hemorrhage (Figure1A, 2A).
Figure 1A: Initial cranial CT scan of the case presented. Note the intraventricular hemorrhage- mostly on the right side. This hemorrhage also extended to the fourth ventricle and caused hydrocephalus. B: Cranial CT scan of the same patient one week after intrathecal urokinase infusion (5000 units every 8 hours for 5 days). Note the almost total resolution of the intraventricular hemorrhage and no evidence of hydrocephalus. There is minimal blood in the right temporal horn. The patient has done well and not required a shunt. No etiology for the spontaneous hemorrhage has been found.
A right-sided frontal ventriculostomy was placed emergently with mild increase in the level of alertness (lethargic, following simple commands). A four vessel cerebral angiogram was performed- this did not show any vascular abnormality. A MRI scan of the brain (with and withour contrast) showed only the IVH, no other abnormality or abnormal enhancement. At this point, 5000 units of IT UK was infused every 8 hours for 5 days. A cranial CT scan was performed 24 hours, 72 hours and then one week after start of IT UK. The 24 scan showed less blood in all the ventricles and the 72 hour scan (figure 2B) showed essentially no blood in the ventricles. The clearance of blood correlated with the patients increased level of alertness. The venrtriculostomy was clamped at one week post-hemorrhage- there were no clinical or radiological signs of hydrocephalus-the ventriculostomy was thus removed. The final scan prior to discharge (Figure 1B) showed no hydrocephalus and minimal blood in the right temporal horn. The patient was awake and alert with no focal neurological deficits. At 6 months followup, this patient continues to do well and is back to her original job. A followup MRI scan of the brain and cerebral angiogram at 6 months post-hemorrhage reveals no abnormalities.
Figure 2A: Initial cranial CT scan of the case presented showing blood in the 4th ventricle. B: Cranial CT scan of the same patient 72 hours after intrathecal administration showing resolution of blood in the 4th ventricle. This correlated with the patient's increase level of alertness. It is important to clear blood from the 4th ventricle in order to improve the level of alertness.
Results:
Three of the four patients with IVH and infusion of IT UK had good neurological
results. In these patients, the average time for clot disappearance was
6 days. None of these three have required a shunt. The patient with a postoperative
IVH did not survive the IVH despite significant clearance of the blood from
the ventricular spaces. This patient, most likely, had additional injury
to her midbrain. The operative procedure in this case was a supracerebellar
infratentorial approach to a large pineal region tumor.
Discussion:
Natural History of the Disease:
The prognosis for cases of severe IVH such as we have treated with IT
UK has been reported to be very poor.(5,6,7) Ikeda et al, in their series
of 81 cases of IVH, reported that of 31 patients whose hemorrhage extended
in all ventricular chambers 25 (81%) died within one week.(6) Little et
al divided their 54 cases of IVH into three basic clinical groups accordng
to the presentation and CT findings.(7) They reported that the group with
massive IVH (usually filling all ventricular chambers) or a primary pontine
hemorrhage with extension into the third and fourth ventricles was characterized
by sudden profound coma, neurological findings of pontomedullary dysfunction
and death within 48 hours of onset.(7)
Management:
Despite the relatively common occurrence of IVH and even severe IVH,
no effective treatment has been reported. Continuous ventricular
drainage has been tried but has not achieved a satisfactory result.(7)
A significant
problem with ventricular drainage is the constant clotting of the ventricular
catheter.
Cisternal irrigation with UK for subarachnoid hemorrhage (SAH) has been used by researchers in an attempt to prevent delayed vasospasm. Shiobara et al used an experimental continuous perfusion system and showed that UK actually resolves a clot in CSF (14); their work supports the effectiveness of infusing UK directly into a ventricle for IVH. Several reports are now in the literature showing the potential effectiveness of IT UK for IVH. (1,9,10,15) Our small series supports the use of IT UK in cases of IVH (especially severe IVH).
Effectiveness of Intrathecal Urokinase:
Treatment of severe IVH with IT UK is dramatic and effective in several
ways. First of all, the outcome of the treatment group in our series and
others was extremely good when compared to the reported prognosis of severe
IVH. In our series, one of four patients did not survive. This unsatisfactory
result was most likely due to the underlying injury to the brain. Other
series have reported unsatisfactory results in cases of IVH from ruptured
aneurysms.(15) In these cases, underlying injury to the brain and ischemia
due to vasospasm may also play a role. Nevertheless, in cases of spontaneous
IVH without any vascular anomaly, results of improvement are dramatic.(1,10,15)
At our institution, a four vessel cerebral angiogram is performed prior
to infusion of IT UK in cases of spontaneous IVH. It is our opinion that
in cases of aneurysms and/ or arteriovenous malformations IT UK should not
be used due to the potential of serious side affects (rebleeding) and lack
of benefit (2,8).
Secondly, this treatment is easy to administer. After the insertion of a ventricular catheter, UK is instilled directly into the ventricles and ventriculostomy is clamped for 10-15 minutes. Third, there was no apparent complication due to this therapy. In our series as well as others IT UK did not cause any additional bleeding, nor did infection occur (1,10,15). It is important to remember, however, that both are potential complications of IT UK. As a matter of fact, Schwarz et al presented 2 cases of secondary hemorrhage after intraventricular fibrinolysis using rt-PA.(13) Fourth, rapid resolution of IVH is observed on CT scans during intraventricular UK infusion. Several authors have reported that a major portion of an IVH disappears spontaneously (i.e. without any therapy) in CT scanning within 3 weeks.(7,16) However, with IT UK the average time required for clot disappearance in both the third and fourth ventricles is 3-5 days.(1,10,15) In our series the average time required for clot disappearance in the third and 4th ventricles was 4 days. This is much shorter than the expected time for spontaneous hematoma resolution and may lead to better outcome as well as less need for a ventriculoperitoneal shunt. It is also important to point out that the resolution of the 4th ventricular blood seems to be a key in decreasing brainstem pressure and increasing the level of alertness of patients.(6,15) This was apparent on our cases, as the clot in the 4th ventricle resolved (see Figure 2 above), three out of four patients became more awake and started following commands more readily. Thus, the reduction of hematoma volume results in decompression of brain tissue around the hematoma with improvement in cerebrospinal fluid flow and possible improvement of periventricular microcirculation.
Conclusions:
Despite the above encouraging results, several questions need to be resolved.
The most important question relates to effective dosage, frequency and timing
of UK infusion. Potential complications of fibrinolytic therapy in general
need to be addressed as well as the role of other agents like rt-PA. Most
authors feel that a controlled study of this promising treatment is warranted.
Nevertheless, we believe that this relatively simple method of treatment
will greatly improve the grave prognosis of severe IVH and should be attempted
in appropriate cases of IVH.